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Abstract:

This invention relates to steroidal solutions for the preparation of
medicaments and drug products useful for treating diseases of the upper
and lower airway passages. Various embodiments of the present invention
provide compositions, compositions and dosage forms with mometasone
furoate in a dissolved state that are suitable for inhalation and can be
used for the treatment of diseases of the upper and/or lower airway
passages.

Claims:

1-96. (canceled)

97. A pharmaceutical composition comprising a mometasone furoate aqueous
solution suitable for inhalation, wherein the concentration of mometasone
furoate is from about 0.02 mcg/ml to about 500 mcg/ml.

98. The composition of claim 97, wherein the concentration of the
mometasone furoate is from about 25 mcg/ml to about 75 mcg/ml.

99. The composition of claim 97, wherein the concentration of the
mometasone furoate is from about 5 mcg/ml to about 50 mcg/ml.

100. The composition of claim 97, wherein the composition comprises at
least one co-solvent.

101. The composition of claim 100, wherein the composition further
comprises at least one co-solvent selected from the group consisting of
propylene glycol, polyethylene glycol 300, polyethylene glycol 400,
ethanol, N--N dimethylacetamide, N-methyl-2-pyrolidone and glycerol and
combinations thereof.

102. The composition of claim 100, wherein the at least one co-solvent is
present in an amount from about 5 to about 15% by weight.

103. The composition of claim 97, wherein the composition comprises at
least one surfactant.

104. The composition of claim 97, wherein the composition comprises at
least one surfactant and at least one oil.

105. The composition of claim 104, wherein the at least one oil is
present in an amount from about 0.01 to about 40% by weight.

106. The composition of claim 104, wherein the at least one oil is
present in an amount from about 1 to about 10% by weight.

107. The composition of claim 97, wherein the composition comprises at
least one oil selected from the group consisting of short, medium or long
chain monoglycerides, diglycerides or triglycerides and combinations
thereof.

108. A pharmaceutical drug product comprising an inhalation device and
the composition of claim 97.

109. The pharmaceutical composition of claim 97 further comprising a
surfactant with a hydrophilic-lipophilic balance value from about 4 to
about 18; optionally an oil; and water.

110. The composition of claim 97, wherein the composition comprises a
microemulsion.

111. The composition of claim 97, wherein the composition comprises a
micellar composition.

112. A method of treating an airway disease comprising administering the
composition of claim 1 once daily to the upper or lower airway passages;
wherein the total daily dose of mometasone furoate is from about 0.04 to
about 200 micrograms.

113. The method of claim 112; wherein the total daily dose of mometasone
furoate is from about 5 to about 50 micrograms of mometasone furoate.

115. A pharmaceutical composition comprising an aqueous solution suitable
for inhalation comprising mometasone furoate in a concentration from
about 5 mcg/ml to about 100 mcg/ml; at least one surfactant in a
concentration from about 0.01 to about 20% by weight; optionally at least
one oil in a concentration from about 0.01 to about 20% by weight; and
water.

116. A pharmaceutical composition comprising a solution suitable for
inhalation, comprising mometasone furoate; at least one excipient having
a hydrophilic moiety and a hydrophobic moiety; and water.

Description:

FIELD OF THE INVENTION

[0001] This invention relates to steroidal compositions for the
preparation of medicaments and drug products useful for treating diseases
of the upper and lower airway passages.

BACKGROUND OF THE INVENTION

[0002] Upper and lower airway conditions such as inflammatory conditions
which include allergic rhinitis and asthma, affect a large amount of the
population. Corticosteroids have been approved to reduce inflammation of
the upper and lower airways. For instance, intranasal corticosteroids
exert a range of effects that inhibit mucosal inflammation, including (1)
reducing inflammatory cell infiltration, (2) decreasing the number of
basophils, eosinophils, neutrophils and mast cells in the nasal passages
and their secretions, (3) reducing release of inflammatory signals from
cells, (4) decreasing mucus production, (5) vasoconstriction and (6)
reducing edema.

[0003] Although corticosteroids have been effective in treating airway
passage diseases, such treating with corticosteroids may often cause
systemic side-effects such as suppression of
hypothalamic-pituitary-adrenocortical ("BPA") axis function by reducing
corticotrophin (ACTH) production, which in turn leads to a reduced
cortisol secretion by the adrenal gland.

[0004] Many efforts have been put forth in designing a safe and
efficacious steroidal composition. Several corticosteroids have been
successfully formulated as aqueous suspensions. However, suspension
compositions may not be completely desirable in some circumstances.
Solution compositions may offer certain advantages under particular
conditions. It has been thought that a steroidal solution composition
would have an unacceptable safety profile because of increased systemic
absorption which could suppress HPA axis function of patients. Thus, it
would be desirable to provide a solution composition suitable for
inhalation that includes a steroidal active pharmaceutical agent and has
an acceptable safety and efficacy profile.

SUMMARY OF THE INVENTION

[0005] Multiple embodiments of the present invention provide
pharmaceutical compositions comprising a steroid solution suitable for
inhalation, wherein the concentration of the steroid is from about 0.1
micrograms (mcg)/ml to about 500 mcg/ml. The solvent used for the
solution may be aqueous or non-aqueous based. Suitable non-aqueous
solvents include propellants such as CFC's or non-CFC's, such as 1,1,1,2
tetrafluoroethance (HFA 134) and 1,1,1,2,3,3,3 heptafluoroethane (HFA
227). Suitable steroids include but are not limited to mometasone furoate
(MF), fluticasone propionate, fluticasone furoate, budesonide,
triamcinolone acetonide, prednisolone, beclomethasone dipropionate,
ciclesonide and flunisolide.

[0006] Several embodiments of the present invention provide solution
compositions that may include a co-solvent system, a complexation system,
a cyclodextrin system, or a lipid based system which may include an
emulsion, microemulsion or micellar composition, that includes a steroid,
such as MF, in dissolved form, in a therapeutically effective amount.

[0007] Various embodiments of the present invention provide for
pharmaceutical compositions comprising a mometasone furoate aqueous
solution suitable for inhalation, wherein the concentration of mometasone
furoate is from about 0.1 mcg/ml to about 500 mcg/ml. Alternatively, the
concentration of the mometasone furoate may be from about 5 mcg/ml to
about 100 mcg/ml, from about 25 mcg/ml to about 75 mcg/ml, from about 50
mcg/ml to about 75 mcg/ml, from about 25 mcg/ml to about 50 mcg/ml, from
about 60 mcg/ml to about 65 mcg/ml, or about 62.5 mcg/ml.

[0008] Various compositions of the present invention may include at least
one co-solvent. The at least one co-solvent may be propylene glycol,
polyethylene glycol 300, polyethylene glycol 400, ethanol and glycerol or
a combination of two or more thereof. A particularly useful co-solvent is
polyethylene glycol. The at least one co-solvent may be present in an
amount from about 0.01 to about 60% by weight or from about 5 to about
15% by weight.

[0009] Various compositions of the present invention may comprise at least
one surfactant or at least one surfactant and at least one oil. The
surfactant may be present in an amount from about 0.01 to about 40% by
weight or from about 1 to about 20%. The oil may be present in an amount
from about 0.01 to about 40% by weight or from about 1 to about 20%.

[0010] Suitable oils include, but are not limited to, short, medium and
long chain mono glycerides, diglycerides and triglycerides. Suitable oils
include, among others, caprylic and capric acid triglyceride and useful
surfactants include polyethylene glycol 660-12 hydroxystearate also known
as macrogol-15-hydroxystearate and marketed with the trade name Solutol
HS 15, and others etc.

[0011] Various compositions of the present invention may include at least
one rheology-modifying agent. Suitable rheology modifying agents include,
but are not limited to, sodium carboxymethyl cellulose, etc.

[0012] Various compositions of the present invention may include at least
one additional active pharmaceutical agent (APA). Suitable additional
APAs include decongestants, antihistamines, beta agonists and
anticholinergics and combinations thereof. A particularly useful
additional APA is a decongestant, such as oxymetazoline.

[0013] Other embodiments of the present invention provide pharmaceutical
drug products that comprise an inhalation device and an aqueous solution
suitable for inhalation comprising mometasone furoate in solution in a
concentration from about 0.1 mcg/ml to about 500 mcg/ml. Other useful
concentrations of MF may be from about 5 mcg/ml to about 100 mcg/ml or
from about 25 mcg/ml to about 75 mcg/ml. Useful inhalation devices
include a nasal spray, soft mist inhaler, pressurized metered dose
inhaler; a nebulizer and the like. Another embodiment of the present
invention provides a method of administering the drug product by applying
the inhalation device to each nostril of the nose and actuating the
inhalation device at least once to each nostril to deliver the solution
to the nasal cavity.

[0014] Still other embodiments of the present invention provide methods of
treating allergic rhinitis which comprise administering a mometasone
furoate solution suitable for inhalation once daily to the upper airway
passages; wherein the total daily dose of mometasone furoate is from
about 0.04 to about 200 micrograms. Other suitable daily dose amounts of
mometasone furoate include from about 5 to about 100 micrograms; from
about 5 to about 50 micrograms; from about 10 to about 45 micrograms or
from about 20 to about 25 micrograms. Such amounts are useful to treat
seasonal or perennial allergic rhinitis.

[0015] Other embodiments of the present invention provide methods of
treating nasal polyposis including administering a mometasone furoate
solution suitable for inhalation once or twice daily to the upper airway
passages; wherein the total daily dose of mometasone furoate is from
about 5 to about 200 micrograms of mometasone furoate. Alternative useful
total daily doses include from about 0.04 to about 100 micrograms of
mometasone furoate, from about 40 to about 50 micrograms of mometasone
furoate.

[0016] Additional embodiments of the present invention provide methods of
treating an airway disease which comprises administering a mometasone
furoate solution suitable for inhalation once daily to the upper or lower
airway passages; wherein the total daily dose of mometasone furoate is
from about 0.04 to about 200 micrograms. The total daily dose of
mometasone furoate may be from about 5 to about 100 micrograms of
mometasone furoate or from about 10 to about 50. Airway diseases that may
be treated with this method include asthma, chronic obstructive pulmonary
disease, sinusitis, allergic rhinitis and/or nasal polyposis and
combinations thereof.

[0017] Still other embodiments provide methods of treating a
corticosteroid-responsive disease of the upper or lower airway passages
in patients afflicted with said disease, which comprises administering to
the surfaces of the passages of the patients a therapeutically effective
amount of a solution of mometasone furoate effective for treating the
disease. The solution may be administered once a day and may contain from
about 0.04 to about 200 micrograms of mometasone furoate, from about 0.04
to about 100 micrograms of mometasone furoate or from about 5 to about 50
micrograms of mometasone furoate.

[0018] Various other embodiments provide methods of administering a
pharmaceutical composition that targets a mometasone furoate solution to
provide a time to maximum plasma concentration (Tmax) of mometasone
furoate of less than one hour post dose. Suitable mometasone furoate
concentration amounts include from about 0.1 mcg/ml to about 500 mcg/ml
from about 5 mcg/ml to about 100 mcg/ml. The total daily dose of
mometasone furoate administered may be from about 5 to about 50
micrograms and the composition may be administered once a day.

[0019] Various other embodiments provide pharmaceutical compositions that
comprise an aqueous solution suitable for inhalation which comprises
mometasone furoate; a surfactant; optionally an oil; and water. The
solution may be a microemulsion or a micellar composition.

[0020] Multiple embodiments provide pharmaceutical compositions which
comprise an aqueous solution suitable for inhalation that comprises
mometasone furoate in a concentration from about 5 mcg/ml to about 100
mcg/ml; at least one surfactant in a concentration from about 0.01 to
about 20%; optionally at least one oil in a concentration from about 0.01
to about 20%; and water. At least one rheology-modifying agent may also
be included.

[0021] Other embodiments provide a pharmaceutical composition comprising
an aqueous solution suitable for inhalation comprising mometasone
furoate; at least one surfactant with a hydrophilic-lipophilic balance
(HLB) value from about 3 to about 18, optionally at least one oil
comprising a fatty acid carbon chain length of C6-C22 fatty
acid; and water.

[0023] Still further embodiments provide pharmaceutical compositions
having an aqueous solution suitable for inhalation, which comprises
mometasone furoate; at least one excipient having a hydrophilic moiety
and a hydrophobic moiety; and water. The excipient may be a cyclodextrin.

[0024] Additional embodiments provide a pharmaceutical composition
comprising a solution suitable for inhalation which includes mometasone
furoate; at least one propellant; at least one co-solvent; optionally at
least one surfactant; wherein the concentration of mometasone furoate is
from about 0.1 mcg/ml to about 500 mcg/ml or alternatively from about 5
mcg/ml to about 100 mcg/ml; from about 25 mcg/ml to about 75 mcg/ml; from
about 60 mcg/ml to about 65 mcg/ml; from about 25 mcg/ml to about 50
mcg/ml; or about 62.5 mcg/ml. Suitable at least one co-solvent include
but are not limited to propylene glycol, polyethylene glycol 300,
polyethylene glycol 400, ethanol, N--N dimethylacetamide,
N-methyl-2-pyrolidone and glycerol and combinations thereof. One
particularly suitable co-solvent, among others, is ethanol, etc. The at
least one co-solvent may be present in an amount from about 0.01 to about
60% by weight or from about 5 to about 15% by weight. The at least one
surfactant may be present in an amount from about 0.01 to about 40% by
weight or from about 1 to about 10% by weight. Another embodiment
provides for a pharmaceutical drug product comprising a metered dose
inhaler canister, valve and this composition. The at least one propellant
may be 1,1,1,2 tetrafluoroethance (1-WA 134) and 1,1,1,2,3,3,3
heptafluoroethane (HFA 227) and combinations thereof.

BRIEF DESCRIPTION OF DRAWINGS

[0025] FIG. 1 Comparison of average human plasma levels over time of the
NASONEX® suspension nasal spray versus the MF microemulsion solution
nasal spray when delivered from the same device at a 200 mcg dose

[0026] FIG. 2 MF of solubility of anhydrous and monohydrate forms of MF in
microemulsions composed of 20% w/w Solutol HS 15 and various oils at
different amounts.

[0028] FIG. 4 The effect of additives on the solubility (mcg/ml) of MF in
various 0.2M sulfobutyl ether beta cyclodextrin (CAPTISOL®) buffered
solutions.

[0029]FIG. 5 Solubility of anhydrous MF (mcg/ml) in various excipients at
10% w/w and 90% water w/w

DETAILED DESCRIPTION

[0030] Several embodiments of the present invention provide compositions
that are steroidal solutions suitable for inhalation. Surprisingly, the
compositions are able to provide aqueous or non-aqueous based solutions
that include a poorly water soluble steroids in a therapeutically
effective amount. The solvent used for the solution may be aqueous or
non-aqueous based. Suitable non-aqueous solvents include propellants such
as CFC's or non-CFC's, such as 1,1,1,2 tetrafluoroethance (HFA 134) and
1,1,1,2,3,3,3 heptafluoroethane (HFA 227). Suitable steroids include but
are not limited to mometasone furoate (MF), fluticasone propionate,
fluticasone furoate, budesonide, triamcinolone acetonide, prednisolone,
beclomethasone dipropionate, ciclesonide and flunisolide. A particularly
useful steroid is mometasone furoate.

[0031] Several embodiments of the present invention provide compositions
including at least one APA, such as a corticosteroid, such as MF, in a
dissolved state. Such compositions with at least one APA in a dissolved
state are referred to as solutions. Compositions including at least one
APA in a dissolved state may be prepared as a solution by any suitable
method including, but not limited to, with the use co-solvents,
complexation agents, cyclodextrins, or a solution may be a lipid based
composition including, but not limited to an emulsion, microemulsion, or
micellar solution.

[0032] Presenting an APA, such as MF, in solution is provided by various
embodiments of the present invention in which the drug is molecularly
dispersed resulted in surprisingly highly absorbed drug products.
Solutions containing MF show a surprisingly rapid increase in blood
levels, see FIG. 1. Rapid absorption at the sites of inflammation may
yield a good therapeutic effect to treat many upper and lower airway
diseases such as nasal symptoms and non-nasal symptoms (including ocular
redness, itching, and tearing, secretions in the throat, irritation of
the throat, coughing, decreased hearing, popping, itching of the ears,
headaches, and/or facial pressure). Increased absorption at the sites of
inflammation may also reduce the onset of action time. The time to
maximum benefit to the patient could also be reduced.

[0033] A lower spray amount may be used, which could reduce spray volume
and lower the daily exposure to preservatives and other inactive
ingredients in the composition. Additionally, a lower spray volume may
reduce the sensation of "dripping"; reducing the patient's tendency to
sniff, which reduces the retention time on the tissue making the drug
appear to be less effective. Less dripping would also increase patient
compliance among those who find this attribute undesirable.

[0034] Suitable solutions include co-solvent compositions where a
co-solvent reduces the dielectric constant of water and facilitates
hydrophobic interactions of drug molecules with the solvent system.
Suitable co-solvents include, but are not limited to, organic solvents
such as ethanol, propylene glycol and polyethylene glycol.

[0035] Suitable solutions may include a cyclodextrin, including but not
limited to, hydroxypropyl-β-cyclodextrin (HPBCD), such as
CAPTISOL®, sulfobutyl ether β-cyclodextrin.

[0036] Suitable solutions include emulsions and microemulsions, which are
systems of water, at least one surfactant and at least one oil. Desirably
they optically appear as a single phase.

[0037] Suitable solutions include micellar solutions, which are typically
optically clear and thermodynamically stable and have enough surfactant
to form aggregates with a lipophilic core and hydrophilic surface.

[0038] Compositions of multiple embodiments of the present invention may
be prepared by using solutions that include polyethylene glycol,
polyethylene glycol 12 oxy-stearate, d-alpha tocopheryl polyethylene
glycol 1000 succinate, polyoxyethylene, sorbitan monooleate, macrogol
hydroxystearate, poloxamers, ethyl laurate, and oils such as short,
medium, and long chain monoglycerides, diglycerides and triglycerides and
combinations thereof.

[0040] Suitable concentration for surfactants will vary depending on the
amount of other excipients and steroid used. Suitable surfactant amounts
include from about 0.001% to about 80% by weight; from 0.01 to about 80%
by weight; from about 0.01 to about 60% by weight; from about 0.01 to
about 40% by weight; from about 0.01 to about 20% by weight; from about
1% to about 15% by weight; from about 1% to about 10% by weight; from
about 1 to about 5% by weight or from about 0.01 to about 5% by weight.

[0041] MF is highly lipophilic. Excipients used to solubilize MF desirably
have a lipophilic component to help it associate with MF. Surfactants are
amphiphilic molecules having both lipophilic and hydrophilic moieties to
form a hydrophobic core containing the oil and hydrophobic drug, when
dispersed in water. If the surfactant concentration is greater than the
critical micelle concentration, the lipophilic cores of the surfactant
aggregate, forming a micelle, which encapsulates the lipophilic molecule.
The hydrophilic components of the surfactant associate with the water.

[0042] In choosing a good surfactant, the percentage of hydrophilic versus
lipophilic moieties on the molecules are desirably balanced. When
evaluating 10% excipients in water, vitamin E TPGS solution was found to
solubilize a high amount of MF. The lipophilic parts of the molecule
included 12 carbon saturated alkyl chains and a benzene ring that could
help solubilize the MF.

[0043] The hydrophilic-lipophilic balance (HLB) of a surfactant is a
measure used to determine the degree to which the surfactant is
hydrophilic or lipophilic. HLB values are determined by calculating
values for the different regions of the molecule, as described by Griffin
and the Davis method. Suitable surfactants typically will have HLB values
from about 3 and above; from about 3 to about 18 or from about 8 to about
18. Oil/water emulsions can be formulated with surfactant/surfactant
blend with HLB values from about 8 to about 18 and water/oil emulsions
can be formulated with HLB values from about 3 to about 6.

[0044] Suitable medium chain triglycerides include, but are not limited
to, caprylic and capric acid triglycerides sold as propylene glycol
dicaprylate/dicaprate sold as MIGLYOL 840 by Sasol and CAPMUL 200
(S)® by Abitech; MIGLYOL 812/MIGLYOL 810@ by Sasol North America; of
caprylic and capric acid linoleic acid triglycerides sold as MYGLYOL
818® by Sasol North America; trigylceride from coconut oil sold as
CAPTEX 300/CAPTEX 850® by Abitech Corp; caprylic/caprylic
triglyceride sold as CAPTEX 355® by Abitech Corp;
caprylic/caprylic/lauric triglyceride sold as CAPTEX 350® by Abitech
Corp; caprylic/caprylic/linoleic triglyceride sold as CAPTEX 810® by
Abitech Corp; caprylic/caprylic/stearic triglyceride sold as CAPTEX
SBE® by Abitech Corp; tricaprylic/Caprylic triglyceride ester sold as
NEOBEE M-5® by Stephan and combinations thereof.

[0046] Suitable concentrations for oils will vary depending on the amount
of other excipients and steroid used. Suitable amounts include from about
0.001% to about 80% by weight; from 0.01 to about 80% by weight; from
about 0.01 to about 60% by weight; from about 0.01 to about 40% by
weight; from about 0.01 to about 20% by weight; from about 1% to about
15% by weight; from about 1% to about 10% by weight; from about 5 to
about 10% by weight or from about 0.01 to about 0.25% by weight.

[0047] Suitable co-solvents include, but are not limited to, propylene
glycol, PEG 300, PEG 400, ethanol, N--N dimethylacetamide (DMA),
N-methyl-2-pyrolidone (NMP), glycerol and combinations thereof. Up to 55%
of the solution may be the co-solvent. Preferably, the co-solvent is in
the range from about 0.01 to about 60% by weight, from about 1 to about
20% by weight, from about 5 to about 20% by weight, from about 1 to about
10% by weight, from about 5 to about 15% by weight or from about 5 to
about 10% by weight. Polyethylene glycol is a particularly useful
solvent.

[0048] Cyclodextrins are cyclic carbohydrates derived from starch. The
unmodified cyclodextrins differ by the number of glucopyranose units
joined together in the cylindrical structure. The parent cyclodextrins
contain 6, 7, or 8 glucopyranose units and are referred to as α-,
β-, and γ-cyclodextrin respectively. Each cyclodextrin subunit
has secondary hydroxyl groups at the 2 and 3 positions and a primary
hydroxyl group at the 6 position. The cyclodextrins may be pictured as
hollow truncated cones with hydrophilic exterior surfaces and hydrophobic
interior cavities. In aqueous solutions, these hydrophobic cavities
provide a haven for hydrophobic organic compounds that can fit all or
part of their structure into these cavities. This process, known as
inclusion complexation, may result in increased apparent aqueous
solubility and stability for the complexed drug. The complex is
stabilized by hydrophobic interactions and does not involve the formation
of any covalent bonds.

[0049] Suitable cyclodextrins include those described in U.S. Pat. Nos.
5,376,645 and 5,134,127 to Stella et al, the entire disclosures of which
are hereby incorporated by reference. The preparation process may
comprise dissolving the cyclodextrin in aqueous base at an appropriate
temperature, e.g., 70° to 80° C., at the highest
concentration possible. For example, to prepare the cyclodextrin
derivatives herein, an amount of an appropriate alkyl sultone,
corresponding to the number of moles of primary CD hydroxyl group
present, is added with vigorous stirring to ensure maximal contact of the
heterogeneous phase. Suitable cyclodextrins include but are not limited
to SBE-7-β-CD (CAPTISOL®), or SBE-4-β-CD available from
Cyclex, Inc.

[0050] Mometasone solution compositions may be prepared by admixing
mometasone furoate with water and other pharmaceutically acceptable
excipients, see Example 1. Solution compositions may contain, inter alia,
water, and/or one or more of the excipients, such as: suspending agents,
e.g., microcrystalline cellulose, sodium carboxymethylcellulose,
hydroxpropyl-methyl cellulose; humectants, e.g. glycerin and propylene
glycol; acids, bases or buffer substances for adjusting the pH, e.g.,
citric acid, sodium citrate, phosphoric acid, sodium phosphate as well as
mixtures of citrate and phosphate buffers; surfactants, e.g. polysorbate
80; and antimicrobial preservatives, e.g., benzalkonium chloride,
phenylethyl alcohol and potassium sorbate. Combinations of any of these
pharmaceutically acceptable excipients may be used also.

[0052] It was discovered that the systemic exposure of mometasone furoate
from a mometasone furoate solution composition nasal spray in humans is
about 9 to about 10 times greater than the systemic exposure from the
NASONEX® mometasone furoate monohydrate suspension composition nasal
spray when delivered at 200 mcg dose from the same type of device. The in
vivo systemic exposure was determined by taking the geometric mean of the
area under the curve (AUC) of the plasma levels at the time points
measured for each subject. The magnitude of this difference in systemic
exposure between an MF solution and an MF suspension is surprising when
considered in view of previous studies conducted on other intranasal
corticosteroids: (a) only a 1-2 times difference in relative
bioavailability was seen between a suspension and solution of
triamcinolone acetonide nasal spray (Hochhaus 2002, J Clin Pharmacol),
and (b) only a 2.5 times difference in relative bioavailability was seen
between a suspension and solution of beclomethasone dipropionate on oral
inhalation (Vanden Burgt 2000 J Allergy Clin Immunol). Thus, the
compositions of the present invention are surprising in view of previous
corticosteroid solutions, which have been prepared but at higher total
daily doses. Due to the dramatic increase in bioavailability of the
solutions of various embodiments of the present invention, the total
daily dose is surprisingly small.

[0053] FIG. 1 compares systemic exposure of MF following administration of
the two compositions to healthy humans described in relation to time. The
in vivo systemic exposure was determined by taking the geometric mean of
the area under the curve (AUC) of the plasma levels at the time points
measured for each subject. When comparing a NASONEX® suspension
(upper line-circles) to a mometasone furoate solution, both at 200 mcg,
(lower line-squares) the MF exposure from a mometasone furoate solution
were significantly greater (about 9 to about 10 times) than from a
NASONEX® suspension even though both compositions were delivered at
the same dose and with the same type of device. At 12 hours after dosing,
concentrations of MF after administration as a solution were still
approximately 6 times higher than the MF concentrations observed after
administration of MF in the form of a suspension. The time to maximum
concentration (Tmax) is less than one hour, which is surprisingly
quick. The maximum concentration (Cmax) is desirably from about 1
picograms(pg)/ml to about 75 pg/ml, from about 5 pg/ml to about 20 pg/ml;
or about 5 pg/ml to about 10 pg/ml.

[0054] Suitable concentrations of mometasone furoate include from about
0.1 micrograms (mcg)/ml to about 500 mcg/ml; 1 mcg/ml to about 500 mcg/ml
from about 5 mcg/ml to about 500 mcg/ml; 5 mcg/ml to about 250 mcg/ml;
from about 5 mcg/ml to about 100 mcg/ml; from about 10 mcg/ml to about
100 mcg/ml; from about 50 mcg/ml to about 100 mcg/ml; from about 25
mcg/ml to about 75 mcg/ml; from about 50 mcg/ml to about 75 mcg/ml; from
about 5 mcg/ml to about 50 mcg/ml; from about 60 mcg/ml to about 65
mcg/ml; about 5 mcg/ml; about 10 mcg/ml; about 15 mcg/ml; about 20
mcg/ml; about 25 mcg/ml; about 30 mcg/ml; about 35 mcg/ml; about 40
mcg/ml; about 45 mcg/ml; about 50 mcg/ml; about 60 mcg/ml; about 65
mcg/ml; or about 70 mcg/ml.

[0055] For example, to deliver a 25 microgram (mcg) dose, a composition
with a mometasone furoate concentration of 62.5 mcg/milliliter (mL) can
be delivered from four sprays of a nasal spray actuator with a spray
volume of about 100 microliter (mcL)/spray actuation.

[0056] Useful total daily doses of mometasone furoate include, but are not
limited to ranges from about 0.04 to about 800 micrograms ("mcg")/day,
about 0.04 to about 400 mcg/day, about 0.04 to about 200 mcg/day, about
0.04 to about 100 mcg/day, about 1 to about 100 mcg/day, about 5 to about
100 mcg/day, about 5 to about 75 mcg/day, about 5 mcg to about 50
mcg/day, from about 10 mcg to about 50 mcg/day, from about 10 mcg to
about 45 mcg/day, from about 10 to about 30 mcg/day, from about 40 to
about 50 mcg/day, from about 15 mcg to about 25 mcg/day, from about 20 to
about 25 mcg/day, about 10 mcg/day, about 15 mcg/day, 20 mcg/day, about
22.5 mcg/day, about 25 mcg/day, about 27.5 mcg/day, about 30 mcg/day
about 40 mcg/day, or about 45 mcg/day.

[0057] Dosing may be one, two, three or four times daily. Particularly
suitable dosing administration is either once daily or twice daily.

[0058] Any suitable form of mometasone furoate may be used, including but
not limited to mometasone furoate anhydrous and mometasone furoate
monohydrate.

[0059] Based on the judgment of the attending clinician, the amount of
mometasone furoate administered and the treatment regimen used will, of
course, be dependent on the age, sex and medical history of the patient
being treated, the severity of the specific asthmatic or non-malignant
pulmonary disease condition and the tolerance of patient to the treatment
regimen as evidenced by local toxicity (e.g., nasal irritation and/or
bleeding) and by systemic side-effects (e.g. cortisol level). Cortisol
(also referred to as hydrocortisone) is the major natural
glucocorticosteroid elaborated by the adrenal cortex.

[0060] Suitable diseases that can be treated include
corticosteroid-responsive disease of the airway passage ways and lungs
which includes those allergic, non-allergic and/or inflammatory diseases
of the upper or lower airway passages or of the lungs which are treatable
by administering corticosteroids such as mometasone furoate. Typical
corticosteroid-responsive diseases include allergic and non-allergic
rhinitis, nasal polyps, chronic obstructive pulmonary disease (COPD) as
well as non-malignant proliferative and inflammatory diseases of the
airways passages and lungs.

[0061] The invention is also useful in treating allergic and non-allergic
rhinitis as well as non-malignant proliferative and/or inflammatory
disease of the airway passages and lungs. Exemplary allergic or
inflammatory conditions of the upper and lower airway passages which can
be treated or relieved according to various embodiments of the present
invention include nasal symptoms associated with allergic rhinitis, such
as seasonal allergic rhinitis, intermittent allergic rhinitis, persistent
allergic rhinitis and/or perennial allergic rhinitis as well as
congestion in moderate to severe seasonal allergic rhinitis patients.
Other conditions that may be treated or prevented include corticosteroid
responsive diseases, nasal polyps, asthma, chronic obstructive pulmonary
disease (COPD), rhinovirus, rhinosinusitis including acute rhinosinusitis
and chronic rhinosinusitis, congestion, total nasal symptoms
(stuffiness/congestion, rhinorrhea, nasal itching, sneezing) and
non-nasal symptoms (itchy/burning eyes, tearing/watery eyes, redness of
the eyes, itching of the ears/palate) and nasal blockage associated with
sinusitis, fungal induced sinusitis, bacterial based sinusitis.

[0062] The term "allergic rhinitis" as used herein means any allergic
reaction of the nasal mucosa and includes hay fever (seasonal allergic
rhinitis) and perennial rhinitis (non-seasonal allergic rhinitis) which
are characterized by seasonal or perennial sneezing, rhinorrhea, nasal
congestion, pruritis and eye itching, redness and tearing.

[0063] The term "non-allergic rhinitis" as used herein means eosinophilic
nonallergic rhinitis which is found in patients with negative skin tests
and those who have numerous eosinophils in their nasal secretions.

[0064] The term "asthma" as used herein includes any asthmatic condition
marked by recurrent attacks of paroxysmal dyspnea (i.e., "reversible
obstructive airway passage disease") with wheezing due to spasmodic
contraction of the bronchi (so called "bronchospasm"). Asthmatic
conditions which may be treated or even prevented in accordance with this
invention include allergic asthma and bronchial allergy characterized by
manifestations in sensitized persons provoked by a variety of factors
including exercise, especially vigorous exercise ("exercise-induced
bronchospasm"), irritant particles (pollen, dust, cotton, cat dander) as
well as mild to moderate asthma, chronic asthma, severe chronic asthma,
severe and unstable asthma, nocturnal asthma, and psychologic stresses.
The invention is particularly useful in preventing the onset of asthma in
mammals e.g., humans afflicted with reversible obstructive disease of the
lower airway passages and lungs as well as exercise-induced bronchospasm.

[0065] The term "non-malignant prolifertive and/or inflammatory disease"
as used herein in reference to the pulmonary system means one or more of
(1) alveolitis, such as extrinsic allergic alveolitis, and drug toxicity
such as caused by, e.g. cytotoxic and/or alkylating agents; (2)
vasculitis such as Wegener's granulomatosis, allergic granulomatosis,
pulmonary hemangiomatosis and idiopathic pulmonary fibrosis, chronic
eosinophilic pneumonia, eosinophilic granuloma and sarcoidoses.

[0066] The phrase "therapeutically effective amount" means that amount of
a medicament which when administered supplies an amount of one or more
pharmaceutically active agents contained therein to provide a therapeutic
benefit in the treatment or management of a disease or disease state.

[0067] Administration may be accomplished utilizing inhalation devices
including but not limited to a nebulizer, a metered pump-spray device,
soft mist inhaler and a pressurized metered dosing inhaler. A single
pressurized metered dose inhaler may be adapted for oral or nasal
inhalation routes simply by switching between an actuator that is
designed for nasal delivery and an actuator designed for oral delivery.

[0068] Solutions may be administered intranasally by inserting an
appropriate device (such as a nasal spray bottle and actuator used to
deliver NASONEX® Nasal Spray) into each nostril. Active drug is then
expelled from the nasal spray device. Efficacy can be generally assessed
in a double blind fashion by a reduction in nasal and non-nasal symptoms
(e.g., sneezing, itching, congestion, and discharge). Other objective
measurements (e.g., nasal peak flow and resistance) can be used as
supportive indices of efficacy. Any suitable pump spray may be used, such
as pump sprays used for NASONEX® as sold by Schering-Plough or
AFRIN® as sold by Schering-Plough.

[0069] Administering mometasone furoate to the surfaces of the airways of
asthmatic patients can maximize the therapeutic index. The term
"therapeutic index", as used herein, means the ratio of local efficacy to
systemic safety.

[0070] Pressurized metered-dose inhalers ("MDI") contain propellants, for
example, chlorofluorocarbon propellants, for example, CFC-11, CFC-12,
hydrofluorocarbon propellants, for example, HFC-134A, 1-1FC-227 or
combinations thereof, to produce a precise quantity of an aerosol of the
medicament contained with the device, which is administered by inhaling
the aerosol nasally, treating the nasal mucosa and/or the sinus cavities.

[0071] A suitable MDI composition will include a propellant such as
1,1,1,2,3,3,3 heptafluoropropane; an excipient, including but not limited
to alcohols, MIGLYOL® 812, MIGLYOL® 840, PEG-400, menthol,
lauroglycol, VERTREL®--245, TRANSCUTOL®, LABRAFAC® Hydro
WL 1219, perfluorocyclobutane, eucalyptus oil, short chain fatty adds,
and combinations thereof; a steroid and optionally a surfactant. MDI's
may be prepared by conventional processes such as cold filling or
pressure filling.

[0072] A "soft-mist" inhaler is a multi-dose, metered aerosol delivery
device typically used to deliver aqueous based solution medicaments to
the lungs via oral inhalation. The aerosol plume that they create is both
slow in velocity and lasts for approximately 6× that of a typical
pMDI (e.g. typically 1-2 sec. vs. milliseconds). An example of such a
device would be Boehringer Ingelheim's (BI) RESPIMAT® which is
currently used to deliver ipatropium bromide to the lungs.

[0073] The medicament compositions of the present invention may also be
administered utilizing a nebulizer device. Typical commercial nebulizer
devices produce dispersions of droplets in gas streams by one of two
methods. Jet nebulizers use a compressed air supply to draw liquid up a
tube and through an orifice by venturi action and introduce it into a
flowing gas stream as droplets suspended therein, after which the fluid
is caused to impact one or more stationary baffles to remove excessively
large droplets. Ultrasonic nebulizers use an electrically driven
transducer to subject a fluid to high-frequency oscillations, producing a
cloud of droplets which can be entrained in a moving gas stream; these
devices are less preferred for delivering suspensions. For instance, from
about 1 to about 4 mL of the mometasone furoate solution may be placed in
a plastic nebulizer container and the patient would inhale for 1-30
minutes. The total dosage placed in such a container would be in the
range of 0.2 to about 100 mcg.

[0074] Also available are hand-held nebulizers which atomize a liquid with
a squeeze bulb air supply, but the more widely used equipment
incorporates an electrically powered compressor or connects to a cylinder
of compressed gas. Although the various devices which are commercially
available vary considerably in their delivery efficiency for a given
medicament since their respective outputs of respirable droplets are far
from identical, any may be used for delivery of the medicaments of the
present invention when a prescriber specifies an exact amount of
medicament composition which is to be charged to each particular device.

[0075] Other embodiments of the present invention provide for
pharmaceutical compositions include combinations of a steroid and at
least one additional APA, including decongestants, antihistamines, beta
agonists and anticholinergics. More particularly, useful combinations of
APAs include mometasone furoate and oxymetazoline, mometasone furoate and
beta agonists such as formoterol, salmeterol, or indacaterol, mometasone
furoate and anticholinergics such as tiotropium, glycopyrrolate, or
ipratropium.

[0077] Useful effective total daily amounts of oxymetazoline include from
about 5 to about 5000 micrograms ("mcg")/day, from about 5 to about 2000
mcg/day, about 12.5 to about 1000 mcg/day, about 25 to about 1000
mcg/day, about 12.5 to about 800 mcg/day, about 12.5 to about 600
mcg/day, about 25 to about 500 mcg/day, 25 to about 400 micrograms, about
50 to about 500, about 50 to about 300 mcg/day, from about 50 to about
200 micrograms, from about 100 to about 300 mcg/day, about 100 mcg/day or
about 200 mcg/day or about 300 mcg/day in single or divided doses. The
total daily dose includes the total amount of drug delivered to both
nostrils. Each nostril may receive 1 or 2 sprays.

[0078] The mometasone furoate administered to treat disease of the upper
or lower airway passages may be used as monotherapy or as adjuvant
therapy with for example cromolyn sodium or nedocromil sodium (available
from Fisons); bronchodilators such as albuterol (available from Schering
Corporation under the PROVENTIL® tradename) or oxymetazoline
(available as AFRIN® from Schering-Plough).

[0080] Depending on the intended application, it may be desirable to
incorporate up to about 5 percent by weight, more typically about 0.5 to
about 5 weight percent, of an additional rheology-modifying agent, such
as a polymer or other material. Useful materials include, without
limitation thereto, sodium carboxymethyl cellulose, algin, carageenans,
carbomers, galactomannans, hydroxypropyl methylcellulose, hydroxypropyl
cellulose, polyethylene glycols, polyvinyl alcohol, polyvinylpyrrolidone,
sodium carboxymethyl chitin, sodium carboxymethyl dextran, sodium
carboxymethyl starch and xanthan gum. Combinations of any two or more of
the foregoing are also useful.

[0081] Mixtures of microcrystalline cellulose and an alkali metal
carboxyalkylcellulose are commercially available, the mixture presently
preferred for use in this invention being sold by FMC Corporation,
Philadelphia, Pa. U.S.A. as AVICEL® RC-591. This material contains
approximately 89 weight percent microcrystalline cellulose and
approximately 11 weight percent sodium carboxymethylcellulose, and is
known for use as a suspending agent in preparing various pharmaceutical
suspensions and emulsions. The compositions of the present invention may
contain at least about 1.0 to about 10 weight percent, or from about 1 to
about 4 weight percent of the mixture of the
cellulose/carboxyalkylcellulose compound mixture.

[0082] A closely related mixture is available from the same source as
AVICEL® RC-581, having the same bulk chemical composition as the
RC-591, and this material is also useful in the invention.
Microcrystalline cellulose and alkali metal carboxyalkylcellulose are
commercially available separately, and can be mixed in desired
proportions for use in the invention, with the amount of microcrystalline
cellulose may be between about 85 and about 95 weight percent of the
mixture for both separately mixed and co-processed mixtures.

[0083] When the compositions of the invention are intended for application
to sensitive mucosal membranes, it may be desirable to adjust the pH to a
relatively neutral value, using an acid or base, unless the natural pH
already is suitable. In general, pH values about 3 to about 8 are
preferred for tissue compatibility; the exact values chosen should also
promote chemical and physical stability of the composition. In some
instances, buffering agents will be included to assist with maintenance
of selected pH values; typical buffers are well known in the art and
include, without limitation thereto, phosphate, citrate and borate salt
systems.

[0084] The compositions may contain any of a number of optional
components, such as humectants, preservatives, antioxidants, chelating
agents, mucoadhesives, and aromatic substances. Humectants, which are
hygroscopic materials such as glycerin, a polyethylene or other glycol, a
polysaccharide and the like act to inhibit water loss from the
composition and may add moisturizing qualities. Useful aromatic
substances include camphor, menthol, eucalyptol and the like, flavors and
fragrances. Preservatives are typically incorporated to establish and
maintain a freedom from pathogenic organisms; representative components
include benzyl alcohol, methylparaben, propylparaben, butylparaben,
chlorobutanol, phenethyl alcohol (which also is a fragrance additive),
phenyl mercuric acetate and benzalkonium chloride.

[0085] Certain aspects of the invention are further described in the
following examples. The descriptions of the embodiments of the invention
have been presented for purpose of illustration and description. They are
not intended to be exhaustive or to limit the invention to the precise
forms disclosed, and obviously many modifications and variations are
possible in light of the above teaching. The term `comprising` is defined
as `including but not limited to`.

[0086] Percentages are expressed on a weight basis, unless the context
clearly indicates otherwise. The mention of any specific drug substance
in this specification or in the claims is intended to encompass not only
the base drug, but also pharmaceutically acceptable salts, esters,
hydrates and other forms of the drug. Where a particular salt or other
form of a drug is mentioned, it is contemplated that other salts or forms
can be substituted.

EXAMPLES

Example 1

Micellar and Microemulsion Compositions

[0087] Various mometasone furoate micellar solutions, such as Compositions
A, C, D and G are prepared by measuring each excipient into a beaker the
given amounts. If needed, the excipients are melted using a water bath
maintained at 65° C. for approximately 30 minutes. The composition
is q.s. to 50 g with water and mixed with an overhead/lightening mixer.
The MF is added based on the concentration for 50 grams and the solutions
are mixed on a lightening mixer for about 7 minutes at 1000 rpm.

[0088] Various MF microemulsion solutions, such as Compositions B, E and
F, are prepared by measuring each excipient into a beaker the given
amounts. If needed, the excipients are melted using a water bath
maintained at 65° C. for approximately 30 minutes. The oil
component is then added and immediately mixed on an overhead/lightening
mixer for 5 minutes at 1000 rpm. The MF is added based on the
concentration for 50 grams and the solutions is mixed on a lightening
mixer for 20 minutes at 1000 rpm. The composition is q.s. to 50 g with
water and mixed with an overhead/lightening mixer.

[0096] To determine the solubility of MF in various solutions, various MF
solutions are prepared by measuring each excipient into a beaker at a 10%
w/w concentration. If needed, the excipients are melted using a water
bath maintained at 65° C. for approximately 30 minutes. The
composition is q.s. to 50 g with water and mixed with an
overhead/lightening mixer. Approximately 50-60 mg of anhydrous mometasone
furoate anhydrous is added into each mixture. The solutions are mixed at
a low speed on a shaker (Eberbacher) for about 48 to about 72 hours.
Approximately 20 mL of each suspension are removed and centrifuged at
1200 rpm for 12 minutes. Approximately 5 mL of the supernatant is
filtered using a 0.22 μm syringe filter. A 1 mL sample is taken from
each filtered sample, diluted, and assayed using an HPLC. The results are
shown in Table 1.

[0097] High solubilities are observed from SOLUTOL® HS 15, polysorbate
80, and CREMOPHOR® RH 40. They have approximately 75% by weight PEG
esterified onto the lipophilic parts of the molecule.

[0098] Vitamin E TPGS has a high solubility of almost 500 μg/g, and
CREMOPHOR® RH 40, SOLUTOL HS® 15, and polysorbate 80 had
solubilities between approximately 180 and 200 μg/mL. Solutions with
10% polyoxamers and polyvinylpyrrolidones (also highly polar), show ME
solubility of less than 30 μg/mL.

Example 3

Microemulsion Solubility Determinations

[0099] The equilibrium solubility of mometasone furoate is determined in
SOLUTOL® HS-15-based microemulsion composition composed of 20% of
SOLUTOL® HS-15 with varying amounts of different oils (FIG. 2, Table
2). An excess amount of the drug is added in the solutions after water
had been added. The vials is shaken over a 72 hour period. The solutions
is centrifuged and filtered at various time intervals prior to analysis
of the samples by HPLC. The drug solubility ranged from 300 mcg/ml to 600
mcg/g. Alternative oils are also explored (Table 3).

[0100] A concentration of 538 mcg/ml of mometasone furoate was achieved
with 5% of MIGLYOL®, 20% w/w of SOLUTOL® HS-15, and 75% phosphate
buffer system (PBS). The concentration was ˜519 mcg/ml in a similar
composition where PBS was replaced with water. To achieve a concentration
of exactly 500 mcg/ml, roughly 5 mg of the drug was weighed and added to
a mixture of 2 g of SOLUTOL® HS-15 and 0.5 g of MIGLYOL® 812,
that was previously mixed using a magnetic stir bar. After the drug was
dissolved in the pre-concentrate, 7.5 g of distilled water was added to
the above mix to formulate a microemulsion of mometasone furoate. The
drug concentration was determined by HPLC, and was found to be -500
mcg/ml. The oil loaded micellar solution composition of mometasone
furoate was physically and chemically stable for at least 2 weeks at
elevated temperature and for at least three cycles of freeze thaw.

[0101] Compositions of mometasone furoate 6 mg/ml were prepared in
duplicate with a 0.05, 0.01, and 0.2 M of four different cyclodextrins:
an unsubstituted gamma cyclodextrin, a sulfobutyl ether (SBE) beta
cyclodextrin (Captisol), and two substituted SBE gamma cyclodextrins.
Only 0.05 and 0.1M cyclodextrins were evaluated for the unsubstituted
gamma cyclodextrin. All compositions were prepared in a 3 mM citrate
buffer at a pH of 4.5. The compositions were placed on a roller mixer
(Stuart Scientific SRT233 rpm rise/fall 16 mm) protected from light and
mixed for about three days. After the three day equilibration, the
compositions were filtered using a 0.22 micrometer PVDF syringe filter
and analyzed by HPLC. The data is shown in FIG. 3 and Table 4, indicating
that the two more substituted gamma sulfobutyl ether cyclodextrins (6.1,
6.2) solubilized greater amounts of MF.

[0103] Metered dose Inhaler (MDI) compositions are prepared by the
following method: oleic acid is added and dissolved in ethanol in an
appropriate pressurized vessel. The MF is then added to the alcohol
mixture and dissolved with high speed agitation or using a homogenizer.
The drug solution is then filled into MDI cans and the propellants are
added by pressure filling.

[0104] A recently concluded clinical study conducted by Schering-Plough
compared the systemic exposure of MF from (A) a commercial NASONEX®
suspension nasal spray and (B) a MF solution delivered by the same device
as used for NASONEX®. The design and methods of the clinical trial.

Clinical Study Design

[0105] The clinical study conducted was a part-randomized, crossover,
open-label study of MF conducted in healthy adult volunteers. A total of
12 male or female subjects were enrolled. On each of the study periods
each subject received 1 of the 2 treatments as shown below in each period
according to their randomized treatment sequences.

[0106] Treatment A MF 200 μg administered as an aqueous suspension from
a NASONEX® Nasal Spray (2 alternating sprays×50 μg per burst
in each nostril)

[0107] Treatment B MF 200 μg administered as a solution using the pump
spray from NASONEX® (2 sprays×50 μg per burst in each
nostril)

[0108] Each of the 4 sprays from the NASONEX® Nasal Spray was
delivered to alternating nostrils to minimize drip/run-off and maximize
nasal cavity deposition (e.g. left nostril, right nostril, left nostril,
right nostril).

[0109] Blood Specimen Collection

[0110] At hours 0 (predose), 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 on Day 1
of each of the 3 study periods, 6.5-mL blood samples (6-mL sample plus
0.5 mL discard) were collected from an indwelling venous catheter from
each subject for pharmacokinetic analysis of MF.

[0111] Assay Method

[0112] MF concentrations in human plasma samples were determined by using
a high-pressure liquid chromatographic-tandem mass spectrometric method.
This proprietary method, that was developed and validated by PPD,
Richmond, Va., was specific for MF, i.e. metabolites of MF were not
detected. The assay sample volume was 1.00 mL of human plasma. The lower
limit of quantification was 0.25 pg/mL.

[0113] Results

[0114] FIG. 1 compares the systemic exposure of MF following
administration of the suspension and solution compositions at the same
dose from the same device. The MF exposure is determined by measuring the
area under the curve (AUC) of the plasma levels at the time points that
were measured. When comparing a NASONEX® suspension (upper
line-circles) to a mometasone furoate solution (lower line-squares), the
MF blood levels from an MF solution were significantly greater (about
1000%) than from a NASONEX® suspension even though both compositions
were delivered at the same dose and with the same type of device. At 12
hours after dosing, concentrations of MF after administration as a
solution were still approximately 600% higher than the MF concentrations
observed after administration of MF in the form of a suspension.